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  Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing.

Mishra, A., Emamgholi, F., Erlangga, Z., Hartleben, B., Unger, K., Wolff, K., et al. (2019). Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing. Carcinogenesis, (in press). doi:10.1093/carcin/bgz108.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-CBB8-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-CBBE-3
Genre: Journal Article

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Mishra, A., Author
Emamgholi, F., Author
Erlangga, Z., Author
Hartleben, B., Author
Unger, K., Author
Wolff, K., Author
Teichmann, U.1, Author              
Kessel, M.2, Author              
Woller, N., Author
Kühnel, F., Author
Dow, L. E., Author
Manns, M. P., Author
Vogel, A., Author
Lowe, S. W., Author
Saborowski, A., Author
Saborowski, M., Author
Affiliations:
1Department of Molecular Cell Biology, MPI for biophysical chemistry, Max Planck Society, ou_578585              
2Research Group of Developmental Biology, MPI for biophysical chemistry, Max Planck Society, ou_578586              

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 Abstract: Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Pre-clinical in vivo model systems exist, but with the advent of precision oncology, murine models with enhanced genetic flexibility are needed to functionally annotate genetic alterations found in the human malignancy. Here, we describe the generation of focal gene disruptions and large chromosomal deletions via inducible and pancreas specific expression of Cas9 in adult mice. Experimental mice are derived on demand directly from genetically engineered embryonic stem cells, without the need for further intercrossing. To provide initial validation of our approach, we show that disruption of the E3 ubiquitin ligase Rnf43 accelerates KrasG12D-dependent tumourigenesis. Moreover, we demonstrate that this system can be used to rapidly interrogate the impact of complex cancer-associated alleles through the generation of a previously unstudied 1.2 megabase deletion surrounding the CKDN2A and CDKN2B tumour suppressors. Thus, our approach is capable of reproducibly generating biallelic and precise loss of large chromosomal fragments that, in conjunction with mutant Kras, leads to development of pancreatic ductal adenocarcinoma with full penetrance.

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Language(s): eng - English
 Dates: 2019-06-06
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1093/carcin/bgz108
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Title: Carcinogenesis
Source Genre: Journal
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